Cardiovascular diseases (e.g., cardiac disease, cerebrovascular disease, and renal disease) caused by hypertension, dyslipidemia, diabetes mellitus, or the like are significant problems for developed countries. Antihypertensive, antidyslipidemic, and antidiabetic drugs are used in the treatment of the diseases hypertension, dyslipidemia, and hyperglycemia, respectively. In the clinical setting, α and β blockers, diuretics, calcium antagonists, ACE inhibitors, and A-II antagonists, etc. are used as antihypertensive drugs; HMG-CoA reductase inhibitors, anion exchange resins, nicotinic acid derivatives, probucol, and fibrates, etc. are used as antidyslipidemic drugs; and insulins, sulfonylureas, metformin, glitazones, and DPP4 inhibitors, etc. are used as antidiabetic drugs. These drugs contribute to the regulation of blood pressure and lipid or glucose levels in the blood. Nonetheless, even the use of these medicaments has not produced a great improvement in the death rates attributed to cardiac disease, cerebrovascular disease, and renal disease. Thus, there is a need for the development of better therapeutic drugs for these diseases.
A direct risk factor for cardiovascular diseases is atherosclerosis associated with thickening of the arterial wall. This thickening is caused by plaque formation resulting from the accumulation of oxidized low-density lipoprotein (hereinafter, referred to as LDL) cholesterol in macrophages and the like in the arterial wall (Non-patent Literatures 1 and 2). This plaque atherosclerosis inhibits blood flow and promotes the formation of blood clots.
The results of many epidemiologic studies indicate that serum concentrations of lipoproteins are associated with diseases such as dyslipidemia and arteriosclerosis (e.g., Non-patent Literature 3). Both an increased concentration of LDL cholesterol in the blood and a decreased concentration of high-density lipoprotein (hereinafter, referred to as HDL) cholesterol in the blood are risk factors for coronary diseases.
In peripheral tissues, HDL promotes efflux of cholesterol, which is in turn esterified by lecithin-cholesterol acetyltransferase (hereinafter, referred to as LCAT) on HDL to produce cholesteryl ester. Increased activity of LCAT promotes cholesterol efflux from macrophages (e.g., Non-patent Literatures 4 and 5). Accordingly, drugs that increase LCAT activity are considered to be useful as medicaments for the treatment or prophylaxis of diseases such as dyslipidemia and arteriosclerosis.
A peptide compound (e.g., Non-patent Literature 6) and, for example, the compound described in Patent Literature 1 as a small molecule, are known as such drugs that increase LCAT activity.
The compounds described in Patent Literatures 2 and 3 are known as compounds having a pyrazolopyridine skeleton.